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Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells

Abstract : Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK cell expansions is challenging. We assessed the value of NK receptor phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (N=46) and a reactive NK group (N=68). We then developed a NK-clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the CLPD-NK patients - constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK exhibited preferentially a CD16low phenotype, displayed more frequently a lower platelet count, and were associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed a whole exome sequencing of sorted, myeloid, T, and NK cells and identified that TET2 mutations were shared by myeloid and NK cells in 3 out of 4 cases. Thus, we hypothesized that TET2 alterations occur early in CLPD-NK disease which could explain a potential link between NK-LGL leukemia and other myeloid malignancies. Finally, we analyzed the transcriptome by RNA-seq of 7 CLPD-NK and evidenced two groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including two TET2-mutated cases, significantly under-expressed genes known to be down-regulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK cell proliferative disorders and potentially new therapeutic opportunities.
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https://hal.archives-ouvertes.fr/hal-03134940
Contributor : Xavier Chard-Hutchinson <>
Submitted on : Friday, February 19, 2021 - 2:31:16 PM
Last modification on : Tuesday, February 23, 2021 - 3:28:46 PM
Long-term archiving on: : Thursday, May 20, 2021 - 7:40:42 PM

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Cedric Pastoret, Fabienne Desmots-Loyer, Gaelle Drillet, Simon Le Gallou, Marie-Laure Boulland, et al.. Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells. Blood, American Society of Hematology, 2021, ⟨10.1182/blood.2020006721⟩. ⟨hal-03134940⟩

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